Potentially functional variants of p14ARF are associated with HPV-positive oropharyngeal cancer patients and survival after definitive chemoradiotherapy

Since p14(ARF) and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14(ARF) may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14(ARF)-rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14(ARF) polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14(ARF) rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14(ARF)-rs3731217 TT genotype had an similar to 7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotypephenotype correlation. Our findings indicate p14(ARF) variants may predict tumor HPV16-positive SCCOP patients and survival.